gene therapy for chinese hemophilia b

Conditions: Hemophilia B

Summary: gt2019001 is a phase 1, open- label, non- randomized, uncontrolled, single dose pilot study to evaluate the safety, tolerability and kinetics of a single intravenous infusion of bbm-h901 in hemophilia b subjects with ≤2iu/dl residual fix levels. bbm-h901 is an adeno-associated viral (aav) vector designed to drive expression of the human factor ix (hfix) transgene and raise circulating levels of endogenous fix.

gt2019001 is a phase 1, open- label, non- randomized, uncontrolled, single dose pilot study to evaluate the safety, tolerability and kinetics of a single intravenous infusion of bbm-h901 in hemophilia b subjects with ≤2iu/dl residual fix levels. three subjects will be enrolled and administered with single infusion of bbm-h901, an aav at one dose level of 5x1012 vg/kg.subjects will provide informed consent and then undergo screening assessments up to 4-8weeks prior administration of bbm-h901. all subjects will undergo 52(+- 2) weeks safety observation and will be encouraged to enroll in an extension study to evaluate long- term safety of bbm-h901 for a total 5 years.the first subject will be dosed at 5x1012 vg/kg and undergo 2 months safety observation of which the data will undergo review by an independent safety committee. the dosing to the second subject will not be performed until acquiring the approve from independent safety committee.

Eligibility criteria:
inclusion criteria: 1. be able to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information (phi) in accordance with national and local privacy regulations; 2. be male and ≥18 years of age; 3. have hemophilia b with ≤2 iu/dl (≤2 %) endogenous fix activity levels as documented by a certified clinical laboratory at the time of screening. if the screening result is \>2% due to insufficient washout from fix protein product, then the severity of hemophilia b may be confirmed by documented historical evidence from a certified clinical laboratory demonstrating ≤2% fix coagulant activity (fix:c) ; 4. have had ≥100 prior exposure days (eds) to any recombinant and/or plasma-derived fix protein products based on historical data from the subject's record/history; 5. a. prophylaxis subjects: have had bleeding events and/or infusions with fix protein products during the last 12 weeks documented in the subjects' medical records; or b. on-demand subjects: have had ≥4 bleeding events in the last 52 weeks and/or chronic hemophilic arthropathy (pain, joint destruction, and loss of range of motion) in one or more joints; 6. have no prior history of hypersensitivity or anaphylaxis associated with any fix or iv immunoglobulin administration; 7. have no measurable fix inhibitor as assessed by laboratory; or documented no prior history of fix inhibitor after 50 eds (family history of inhibitors will not exclude the subject) and no clinical signs or symptoms of decreased response to fix administration; 8. have acceptable laboratory values: 1. hemoglobin ≥11 g/dl; 2. platelets ≥100,000 cells/μl; 3. ast, alt, alkaline phosphatase ≤2x upper limit of normal at the testing laboratory; 4. bilirubin ≤3x uln ; 5. creatinine ≤2.0 mg/dl. 9. agree to use reliable barrier contraception until 52 weeks and semen samples after the administration of bbm- h901 are negative for vector sequences. exclusion criteria: 1. have active hepatitis b or c, and hbsag, hepatitis b core antibody, hepatitis b virus-dna positivity or hepatitis c virus-rna viral load positivity, respectively. negative viral assays in two samples, collected at least six months apart, will be required to be considered negative. both natural clearers and those who have cleared hepatitis c virus on antiviral therapy are eligible; 2. currently on antiviral therapy for hepatitis b or c; 3. have significant underlying liver disease, as defined by a preexisting diagnosis of portal hypertension, splenomegaly, encephalopathy, reduction below normal limits of serum albumin or evidence of significant liver fibrosis (fibrosis stage ≥ 3) within the past 6 months prior to or at screening as determined by any of the following diagnostic modalities: ast-to-platelet ratio index (apri) \>1; 4. have serological evidence of hiv-1 or hiv-2 with cd4 counts ≤200/mm3. subjects who are hiv-positive and stable, with an adequate cd4 count (\>200/mm3) and undetectable viral load (\<50 gc/ml) measured twice in the six months prior to enrollment, on an antiretroviral drug regimen are eligible to enroll; 5. have anti-bbm-h901 neutralizing antibody titers ≥1:5; 6. have history of chronic infection or other chronic disease that the investigator considers to constitute an unacceptable risk; 7. have participated in a previous gene therapy research trial within the last 52 weeks or in a clinical study with an investigational drug within the last 12 weeks; 8. any concurrent clinically significant major disease or any other condition that, in the opinion of the investigator, makes the subject unsuitable for participation in the study; 9. unable or unwilling to comply with the schedule of visits and study assessments described in the clinical protocol.

Keywords: hemophilia b gene therapy adeno-associated viruses